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Straub Lab

Nolan Carew

I am currently interested in investigating the mechanisms the abrogate oxidative stress during heart failure.
 

Joseph Galley

Discovery of novel mechanisms of vascular tone regulation through FoxO transcription factors
 

Heidi Schmidt

I am interested in studying the role of xanthine oxidase under conditions of excess circulating free heme in hemolytic diseases such as sickle cell disease.
 

Adam C. Straub, PhD

Our Focus

The overarching goal of the Straub laboratory is to investigate novel redox-controlled cell signaling mechanisms that regulate endothelial and smooth muscle cell biology and cell-cell communication in the microcirculation.  Our investigations focus on two important pathways: 1) the mechanisms by which endothelial cell expressed hemoglobin a regulates nitric oxide signaling in the blood vessel wall and 2) the mechanisms by which the intracellular nicotinamide phosphoribosyltransferase (NAMPT) pathway controls basic redox signaling functions in vascular cells. 

 

Mechanisms of hemoglobin a-regulated nitric oxide signaling in endothelial cells.

Nitric oxide (NO) signaling regulates arterial vascular reactivity in the microcirculation to control peripheral vascular resistance and thus blood pressure.  Recently, it was reported for the first time that hemoglobin a is expressed in arterial endothelial cells (ECs), where it is in complex with endothelial nitric oxide synthase (eNOS) (Straub et al., Nature 2012). It was demonstrated that endothelial hemoglobin a is enriched at the myoendothelial junction, the point where endothelial cells and smooth muscle cells make contact in resistance arteries and arterioles, where it regulates the effect of NO signaling on vascular reactivity.  Mechanistically, hemoglobin a heme iron in the Fe3+ state permits active NO signaling, and this signaling is shut off when hemoglobin a is reduced to the Fe2+ state by endothelial cytochrome B5 reductase 3 (CytB5R3).  These data reveal a novel paradigm by which the regulation of intracellular hemoglobin oxidation controls NOS signaling in non-erythroid cells. This paradigm may be relevant to a broad range of other somatic cells discovered to express hemoglobin (i.e. neurons, renal mesangial cells, macrophages, sympathetic nerves, hepatocytes, alveolar epithelial cells, and endometrial cells) and also known to express NOS isoforms. Our studies will be a direct outgrowth of this work, where we will focus on the molecular, cellular, and in vivo contribution of somatic hemoglobins and CytB5Rs as it pertains to vascular physiology and disease.

 

NAD regulation and the NAMPT pathway in vascular physiology and disease

Nicotinamide adenine dinucleotide (NAD) is a fundamentally important molecule critical for many redox reactions in biology.  Interestingly, the regulation of NAD+ and NAD(H) is dependent on cell type, which are governed by multiple mechanisms. One mechanism that regulates NAD+ levels is NAMPT, also known as pre-B cell colony factor (PBEF) or visfatin.  Existing both as an extracellular and intracellular protein, NAMPT is a rate-limiting enzyme in the NAD+ biosynthesis pathway and is vital for embryonic development since homozygous knockout mice are embryonic lethal (Revollo et al, 2007).  The extracellular form of NAMPT stimulates both NAD+ and non-NAD+ signaling pathways in vascular cells, while intracellular NAD+ generated by NAMPT has been shown to regulate vascular cell longevity and protection against ischemia/reperfusion in the heart through a surtuin-1 dependent pathway (van der Veer et al 2007, Hsu et al, 2009).  Although it has been established that intracellular NAMPT can regulate NAD+ levels, the downstream signaling pathways relying on this enzyme with regards to resistance arterial tone regulation remains elusive.  Our goal is to better understand the role(s) of this enzyme in the microcirculation and in vascular biology in general.

http://www.straublab.pitt.edu/


Headshot of Joseph Galley
Joseph Galley
Predoctoral Fellow

Headshot of Heidi Schmidt
Heidi Schmidt
Predoctoral Fellow

Headshot of Adam C. Straub, PhD
Adam C. Straub, PhD
Associate Professor & Vice Chair, Research

Nolan Carew

Journal Articles

Rahaman MM, Nguyen AT, Miller MP, Hahn SA, Sparacino-Watkins C, Jobbagy S, Carew NT, Cantu-Medellin N, Wood KC, Baty CJ, Schopfer FJ, Kelley EE, Gladwin MT, Martin E, Straub AC. Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling. Circ Res. 2017 Jul 7;121(2):137-148. doi: 10.1161/CIRCRESAHA.117.310705. Epub 2017 Jun 5. PMID: 28584062 PMCID: PMC5527687
 
Smith Sm And Carew Nt*, Milcarek C. Rna Polymerases In Plasma Cells Trav-Ell2 The Beat Of A Different Drum. World J Immunol 2015; 5(3): 99-112 *Co-First Authors
 
Nelson Am, Carew Nt, Smith Sm, Milcarek C (2018) Rna Splicing In The Transition From B Cells To Antibody Secreting Cells; The Influences Of Ell2, Snrna, And Er Stress. Second Draft Under Review, J. Immun.
 

Joseph Galley

Journal Articles

Galley JC, Hahn SA, Miller MP, Durgin BG, Jackson EK, Stocker SD, Straub AC. Angiotensin II augments renal vascular smooth muscle soluble GC expression via an AT1 receptor-forkhead box subclass O transcription factor signalling axis.  Br J Pharmacol. 2021 May 7. doi: 10.1111/bph.15522. Online ahead of print. PMID: 33963547

 
Galley JC, Durgin BG, Miller MP, Hahn SA, Yuan S, Wood KC, Straub AC. Antagonism of Forkhead Box Subclass O Transcription Factors Elicits Loss of Soluble Guanylyl Cyclase Expression.  Mol Pharmacol. 2019 Jun;95(6):629-637. doi: 10.1124/mol.118.115386. Epub 2019 Apr 15. PMID: 30988014   PMCID: PMC6527398
 
Alvarez RA, Miller MP, Hahn SA, Galley JC, Bauer E, Bachman T, Hu J, Sembrat J, Goncharov D, Mora AL, Rojas M, Goncharova E, Straub AC.   Targeting Pulmonary Endothelial Hemoglobin α Improves Nitric Oxide Signaling and Reverses Pulmonary Artery Endothelial Dysfunction.  Am J Respir Cell Mol Biol. 2017 Dec;57(6):733-744. doi: 10.1165/rcmb.2016-0418OC. PMID: 28800253  PMCID: PMC5765416

 
Galley JC, Straub AC.   Redox Control of Vascular Function.  Arterioscler Thromb Vasc Biol. 2017 Dec;37(12):e178-e184. doi: 10.1161/ATVBAHA.117.309945. PMID: 29162599  PMCID: PMC5751756
 

Heidi Schmidt

Journal Articles

Lewis, S.E., Rosencrance, C.B., DeVallance, E., Giromini, A., Williams, X.M., Oh, J., Schmidt, H.M., Straub, A.C., Chantler, P.D., Patel, R.P., Kelley, E.E., “Human and Rodent Red Blood Cells do not Demonstrate Xanthine Oxidase Activity or XO-Catalyzed Nitrite Reduction to NO,” Free Radical Biology and Medicine (2021).
 
Dosunmu-Ogunbi, A., Galley, J.C., Yuan, S., Schmidt, H.M., Wood, K.C., Straub, A.C., “Redox Switches Controlling Nitric Oxide Signaling in the Resistance Vasculature and Implications for Blood Pressure Regulation,” Hypertension (2021)
 
Yuan, S., Schmidt, H.M., Wood, K.C., Straub, A.C., “Coenzyme Q in cellular redox regulation and clinical heart failure”, Free Radical Biology and Medicine. https://doi.org/10.1016/j.freeradbiomed.2021.03.011 (2021).
 
Schmidt HM, Wood KC, Lewis SE, Hahn SA, Williams XM, McMahon B, Baust JJ, Yuan S, Bachman TN, Wang Y, Oh JY, Ghosh S, Ofori-Acquah SF, Lebensburger JD, Patel RP, Du J, Vitturi DA, Kelley EE, Straub AC. Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease.   Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):769-782. doi: 10.1161/ATVBAHA.120.315081. Epub 2020 Dec 3. PMID: 33267657   PMCID: PMC8185582
Kikuchi A, Singh S, Poddar M, Nakao T, Schmidt HM, Gayden JD, Sato T, Arteel GE, Monga SP.  Hepatic Stellate Cell-Specific Platelet-Derived Growth Factor Receptor-α Loss Reduces Fibrosis and Promotes Repair after Hepatocellular Injury.   Am J Pathol. 2020 Oct;190(10):2080-2094. doi: 10.1016/j.ajpath.2020.06.006. Epub 2020 Jun 29. PMID: 32615075  PMCID: PMC7527859
 
Kikuchi, A., Singh, S., Poddar, M., Nakao, T., Schmidt, H.M., Gayden, J.D., Sato, T., Arteel, G.E., Monga, S.P., “Hepatic stellate cell-specific platelet-derived growth factor receptor α loss reduces fibrosis and promotes repair following hepatocellular injury,” The American Journal of Pathology. doi: 10.1016/j.ajpath.2020.06.006. (2020)
 
Wood KC, Durgin BG, Schmidt HM, Hahn SA, Baust JJ, Bachman T, Vitturi DA, Ghosh S, Ofori-Acquah SF, Mora AL, Gladwin MT, Straub AC.  Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice.  Blood Adv. 2019 Dec 10;3(23):4104-4116. doi: 10.1182/bloodadvances.2019000621. PMID: 31821458  PMCID: PMC6963246
Wood, K.C., Durgin, B.G., Schmidt, H.M., Hahn, S.A., Baust, J.J., Bachman, T., Vitturi, D.A., Ghosh, S., Ofori-Acquah, S.F., Mora, A.L., Gladwin, M.T., and Straub, A.C., “Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice,” Blood Advances. doi: 10.1182/bloodadvances.2019000621 (2019)
 
Durgin BG, Hahn SA, Schmidt HM, Miller MP, Hafeez N, Mathar I, Freitag D, Sandner P, Straub AC.   Loss of smooth muscle CYB5R3 amplifies angiotensin II-induced hypertension by increasing sGC heme oxidation. JCI Insight. 2019 Oct 3;4(19):e129183. doi: 10.1172/jci.insight.129183. PMID: 31487266  PMCID: PMC6795404
 
Durgin, B.G., Hahn, S.A., Schmidt, H.M., Miller, M.P., Hafeez, N., Mathar, I., Freitag, D., Sandner, P., and Straub, A.C., “Loss of smooth muscle CYB5R3 amplifies angiotensin II-induced hypertension by increasing sGC heme oxidation,” JCI Insight. doi: 10.1172/jci.insight.129183. (2019)
 
Schmidt, H.M., Kelley, E.E., Straub, A.S., “The impact of xanthine oxidase (XO) on hemolytic diseases,” Redox Biology. doi: 10.1016/j.redox.2018.101072 (2018)
 
Schmidt HM, Kelley EE, Straub AC.   The impact of xanthine oxidase (XO) on hemolytic diseases.  Redox Biol. 2019 Feb;21:101072. doi: 10.1016/j.redox.2018.101072. Epub 2018 Dec 10. PMID: 30580157  PMCID: PMC6305892
 

Adam C. Straub, PhD

Journal Articles

Straub AC, AW Lohman, M Billaud, SR Johnstone, MY Lee, P Schoppee-Bortz, AK Best, ST Dwyer, L Columbus, B Gaston and BE Isakson.  Endothelial cell expression of hemoglobin alpha regulates nitric oxide signaling.  Nature 491:473-477, 2012.
Straub AC, M Billaud, SR Johnstone, AK Best, S Yemen, ST Dwyer, R Looft-Wilson, JJ Lysiak, B Gaston, LA Palmer and BE Isakson.  Compartmentalized connexin 43 S-nitrosylation/denitrosylation regulates heterocellular communication in the vessel wall.  Arterioscler Thromb Vasc Biol 31:399-407, 2011.
Billaud M, AW Lohman, AC Straub, R Looft-Wilson, SR Johnstone, CA Araj, AK Best, F Chekeni, K Ravichandran, S Penuela, D Laird and BE Isakson.  Pannexin 1 regulates alpha 1-adrenergic receptor-mediated vasoconstriction.  Circ Res 109:80-85, 2011.
Heberlein K, AC Straub, AK Best, RC Looft-Wilson and BE Isakson.  Plasminogen activator inhibitor-1 can regulate myoendothelial junction formation.  Circ Res 106:1092-1102, 2010.
Straub AC, KA Clark, MA Ross, AG Chandra, S Li, X Gao, PJ Pagano, DB Stolz and A Barchowsky.  Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH-oxidase generated superoxide.  J Clin Invest 118:3980-3989, 2008.
Straub AC, DB Stolz, MA Ross, A Hernandez-Zavala, NV Soucy, LR Klei and A Barchowsky.  Arsenic stimulates sinusoidal endothelial  cell capillarization and vessel remodeling in mouse liver.  Hepatology 45:205-212, 2007.